1. Field of the Invention
This invention relates generally to an apparatus and method for delivering and detecting electrical signals to/from the patient's brain. In one embodiment, this invention also relates to an apparatus and method for performing ablative surgery on a patient. In particular the invention is concerned with an apparatus and method for performing brain surgery; and more particularly the invention is concerned with an apparatus and method for performing brain surgery by monitoring and selectively inactivating specific regions within the brain. The invention is also concerned with an apparatus and method for delivering therapeutic drugs, and more particularly is concerned with an apparatus and method for delivering therapeutic drug to a specific region within a patient's brain tissues, by monitoring and selectively delivering a drug to the target tissue. In one embodiment, this invention also relates to an apparatus and method for selective electrical stimulation of a patient's hypothalamus for the purpose of appetite regulation. In yet another embodiment, this invention relates to an apparatus and method for localized drug treatment for the purpose of appetite regulation by drug microinfusion into certain regions of the hypothalamus.
2. Background of the Related Art
Prior to the nineteenth century, physicians and scientists believed the brain was an organ with functional properties distributed equally through its mass. Localization of specific functions within subregions of the brain was first demonstrated in the 1800's, and provided the fundamental conceptual framework for all of modern neuroscience and neurosurgery.
As it became clear that brain subregions served specific functions such as movement of the extremities, and touch sensation, it was also noted that direct electrical stimulation of the surface of these brain regions could cause partial reproduction of these functions. Morgan, J. P., “The first reported case of electrical stimulation of the human brain,” J. History of Medicine, January 1982:51–63, 1982; Walker, A. E., “The development of the concept of cerebral localization in the nineteenth century,” Bull. Hist. Med., 31:99–121, 1957.
Brain Mapping Studies
The most extensive work on electrical stimulation “mapping” of the human brain surface was carried out over several decades by Dr. Wilder Penfield, a neurosurgeon and physiologist at the Montreal Neurological Institute, mostly during the early to mid-1900's. He made precise observations during cortical stimulation of hundreds of awake patients undergoing brain surgery for intractable epilepsy. Among his many findings, he noted that stimulation of the visual and hearing areas of the brain reproducibly caused the patients to experience visual and auditory phenomena. Penfield, W. et al., “Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation,” Brain 60:389443, 1937; Penfield, W. et al., Epilepsy and the Functional Anatomy of the Human Brain, London: Churchill, 1954; Penfield, W. et al., “The brain's record of auditory and visual experience,” Brain, 86:595–696, 1963. Following the results of early human brain mapping studies, electrical stimulation of sensory brain regions to restore lost function was a logical therapeutic extrapolation. Drs. Brindley and Lewin of the University of Cambridge were the first to reduce the concept to practice by implanting a patient with a visual cortex neural prosthetic device. Brindley, G. S. et al., “The sensations produced by electrical stimulation of the visual cortex,” J. Physiol. 196:479493, 1968. Their device consisted of an array of thin, flat electrodes placed on the surface of the visual cortex. The electrodes were remotely controlled with radio signals. A similar system was later tested at the University of Utah by Dr. Dobelle and colleagues. Dobelle, W. H. et al., “Artificial vision for the blind: stimulation of the visual cortex offers hope for a functional prosthesis,” Science 183:440444, 1974.
Findings from these early British and American studies were consistent. Patients reliably perceived flashes of light (phosphenes) during periods of electrical stimulation, and simple patterns of phosphenes could be generated by simultaneously activating multiple contacts. While these findings strongly suggested the eventual feasibility of a cortical visual prosthetic device, many important design problems were insurmountable at that time.
Among these were an inability to precisely stimulate very small volumes of brain, the requirement for high stimulation currents to induce phosphenes, and an inability to access the patient's full “visual space” with the large array of surface electrodes used. Additionally, there were no miniature video cameras and small, powerful computers at the time capable of converting visual images into complex electrical stimulation sequences at ultra high speed.
Penetrating Electrodes as Neural Prostheses
The University of Utah has discontinued visual cortex prostheses research. However, the concept has been pursued at NIH where significant additional advances have been made. Their most important discovery to date relates to the use of needle shaped penetrating depth electrodes instead of flat surface stimulating electrodes. Bak, M., et al., “Visual sensations produced by intracortical microstimulation of the human occipital cortex,” Med. Biol. Eng. Comput., 28:257–259, 1990. Penetrating electrodes represent a major design improvement. They are placed within the brain tissue itself so there is optimal surface contact with elements of the brain that are targeted for stimulation. As a result, patients perceive visual phosphenes with approximately a thousand-fold less stimulation current than that required when surface electrodes are used. This allows for safe, chronic stimulation of very small discrete volumes of brain.
Additionally, penetrating electrodes transform what was in the past a two dimensional implant-brain interface (flat disks on the surface of the brain) into a three dimensional interface (multiple needle-like electrodes in parallel extending from the surface into the brain substance), which vastly increases the device's access to stimulation targets below the surface. To use a television screen analogy, a two dimensional surface-electrode array may have the potential of generating an image on the “screen” composed of approximately one hundred discreet dots (“pixels”), whereas a three-dimensional array would potentially generate an image with many thousands of dots. The huge potential increase in image resolution would be achieved using a small fraction of the stimulation currents used in the past.
Penetrating electrodes have the potential to markedly increase both image quality and the safety of the stimulation process. Human experimental studies continue at the NIH campus. Extramural NIH funding is also directed at supporting engineering research on penetrating electrodes optimally suited for neural prosthetics applications. The University of Michigan, for example, has made use of computer-chip manufacturing techniques to synthesize exquisitely small electrode arrays. The etched electrical contacts on these devices are so small that the distance separating adjacent contacts can be in the range of 50 micrometers, approximately the diameter of two nerve cell bodies. Drake, K. L. et al., “Performance of planar multisite microprobes in recording extracellular single-unit intracortical activity,” IEEE Trans. BME, 35:719–732, 1988.
During the 1970's the neural prosthetics group at the University of Utah not only explored the feasibility of a visual cortex neural prosthetic device, but carried out experiments in auditory cortex stimulation as well. Led by Dr. Dobelle, they formed a mobile research group that traveled to surgical centers throughout the United States when suitable experimental subjects were identified. These were patients who required temporal lobe surgery for tumor removal or treatment of intractable epilepsy, and who agreed to participate in the experimental protocol. Dobelle, W. H. et al., “A prosthesis for the deaf based on cortical stimulation,” Ann. Otol, 82:445463, 1973.
The primary auditory region of the human brain is buried deep within the Sylvian fissure. It is not visible from the brain surface and its exact location varies slightly from one person to the next. MRI and CT scanners were not invented at the time of Dr. Dobelle's experiments so the anatomy of the patients' auditory cortex could not be studied prior to surgery, and this region could only be visualized with difficulty in the operating room after the Sylvian fissure was surgically dissected. Once the buried auditory cortex was exposed, surface stimulating electrodes were placed by hand over the area thought to be auditory cortex and the brain was stimulated in a fashion similar to that used to generate visual phosphenes.
Reproducible sound sensations were generated in the experimental subjects. Though these preliminary findings were encouraging, a range of limitations precluded further work by this group. Among the more daunting problems the Utah group faced were recruiting suitable patients for the experimental study and obtaining good stimulation characteristics from the experimental surface electrodes. The minimal stimulation threshold for eliciting sound sensations was found to be 6 milliamperes, which is too high to be tolerated chronically and is thousands of times greater than currents found subsequently to be required to generate phosphenes in visual cortex using penetrating electrodes.
Recent advances in MRI and computer technology now allow detailed preoperative imaging of human auditory cortex.
Another major technical innovation developed since the time of Dr. Dobelle's early experiments is the cochlear implant. An important aspect of the cochlear implant technology, which is now highly refined, involves transducing sound into complex electrical stimulation sequences. This large body of technical knowledge developed over the last twenty years will be directly applicable to the auditory cortex prosthetic device and aid immeasurably in its research and development.
Normal Hearing
Mechanisms of human hearing are reviewed briefly to provide a framework for discussion of auditory neural prosthetic devices. The auditory system is composed of many structural components that are connected extensively by bundles of nerve fibers. The system's overall function is to enable humans to extract usable information from sounds in the environment. By transducing acoustic signals into electrical signals that can then be processed in the brain, humans are able to discriminate amongst a wide range of sounds with great precision.
FIGS. 1A and 1B show a side and front view of areas involved in the hearing process. In particular, the normal transduction of sound waves into electrical signals occurs in cochlea 110, a part of the inner ear located within temporal bone (not shown). Cochlea 110 is tonotopically organized, meaning different parts of cochlea 110 respond optimally to different tones; one end of cochlea 110 responds best to high frequency tones, while the other end responds best to low frequency tones. Cochlea 110 converts the tones to electrical signals which are then received by cochlea nucleus 116. This converted information is passed from cochlea 110 into brain stem 114 by way of electrical signals carried along the acoustic nerve and in particular, cranial nerve VIII (not shown).
The next important auditory structure encountered is cochlea nucleus 116 in the brain stem 114. As the acoustic nerve leaves the temporal bone and enters skull cavity 122, it penetrates brain stem 114 and relays coded signals to cochlear nucleus 116, which is also tonotopically organized. Through many fiber-tract interconnections and relays (not shown), sound signals are analyzed at sites throughout brain stem 114 and thalamus 126. The final signal analysis site is primary auditory cortex 150 situated in temporal lobe 156.
The mechanisms of function of these various structures has also been extensively studied. The function of cochlea 110 is the most well-understood and the function of primary auditory cortex 150 is the least understood. For example, removal of the cochlea 110 results in complete deafness in ear 160, whereas removal of primary auditory cortex 150 from one side produces minimal deficits. Despite extensive neural connections with other components of the auditory system, primary auditory cortex 150 does not appear to be necessary for many auditory functions.
Cochlear Implant
Cochlear implants were designed for patients who are deaf as a result of loss of the cochlea's sound transduction mechanism. Implant candidates must have an intact acoustic nerve capable of carrying electrical signals away from the middle ear into the brain stem. The device converts sound waves into electrical signals which are delivered through a multi-contact stimulating electrode. The stimulating electrode is surgically inserted by an otolaryngologist into the damaged cochlea. Activation of the contacts stimulates acoustic nerve terminals which would normally be activated by the cochlear sound transduction mechanism. The patient perceives sound as the coded electrical signal is carried from the middle ear into the brain by the acoustic nerve. Cohen, N. L. et al., “A prospective, randomized study of cochlear implants,” N. Engl. J. Med., 328:233–7, 1993.
In patients with hearing loss caused by dysfunction at the level of the cochlea, cochlear implants can be remarkably effective in restoring hearing. For example, some previously deaf patients are able to understand conversations over the telephone following insertion of a cochlear implant.
Cochlear implants are surgically placed in the middle ear which is situated in the temporal bone. In patients who are already deaf, there is very little chance of any additional injury being caused by placement of a cochlear implant; they are very safe devices. Because of the low health risk associated with placing cochlear implants, obtaining experimental subjects during the early development stage was not difficult. In this setting design improvements occurred rapidly.
Cochlear Nucleus Implant
Patients are not candidates for cochlear implants if their hearing loss results from damage in auditory regions other than the cochlea. Because the first auditory relay station “downstream” from the cochlea and auditory nerve is the brainstem cochlear nucleus, this structure is a logical candidate for consideration as an implantation site. This approach was first developed at the House Ear Institute. Eisenberg, L. S. et al., “Electrical stimulation of the auditory brainstem structure in deafened adults,” J. Rehab. Res. 24:9–22, 1987; Hitselberger, W. E. et al., “Cochlear nucleus implant,” Otolaryngol. Head Neck Surg., 92:52–54, 1984. As is the case with cochlear implants, sound waves are translated into a complex electrical code F. The implant's stimulation terminals are placed up against the cochlear nucleus, and the patient perceives sounds when the system is activated.
Data on efficacy is limited because relatively few patients have been tested with this device. Early findings demonstrate, however, that some degree of useful hearing is restored using this device. Environmental sounds such as a knock at the door and a telephone ringing have been detected by patients with a cochlear nucleus implant, and this improved auditory function has increased patients' ability to live independently.
Although work in the visual cortex demonstrates that central nervous system penetrating electrodes are significantly more effective than surface electrodes, use of penetrating electrodes in the cochlear nucleus has been discontinued for safety reasons described below.
For several reasons, there is significantly more risk associated with cochlear nucleus implants than cochlear implants. The cochlear nucleus is situated in the brain stem; a very sensitive and vital structure. Neurosurgical procedures in the brain stem are among the most difficult and dangerous operations performed. Infiltrating tumors within the substance of the brainstem, for example, are usually considered surgically inoperable. Surgical manipulation or injury of brainstem elements can cause devastating complications, including loss of normal swallowing functions, loss of control of eye movements, paralysis, coma, and death.
Because of their internationally renowned acoustic neuroma practice, doctors at the House Ear Institute are among the most experienced surgeons in the world at gaining surgical access to the brainstem surface. Acoustic neuromas are tumors arising from the supporting cells of the acoustic nerve. As they enlarge, these tumors expand into the cranial cavity and press up against the brainstem. Patients typically present with hearing loss, and a number of surgical approaches have been developed by otolaryngologists and neurosurgeons to remove these lesions.
Surgeons at the House Ear Institute have played a pioneering role in acoustic neuroma surgery and now routinely perform operations where the tumor is safely removed and the brainstem surface is visualized. They have placed cochlear nucleus implants in deaf patients who have lost function of both acoustic nerves and are undergoing removal of an acoustic neuroma. This affords access to the brainstem surface during a medically necessary procedure.
The first cochlear nucleus implant used penetrating electrodes. These functioned well initially, however within two months they had migrated further into the brainstem, causing tingling sensation in the patient's hip as adjacent fiber tracts were inadvertently stimulated. This system was removed and surface electrodes have been used for cochlear nucleus implants since that time. Risks of implanting a cochlear nucleus device are such that patients are only candidates for implantation if they require surgery in that area of the brainstem for some other, usually life threatening reason.
It is difficult to find suitable patients for implantation and testing of cochlear nucleus implants. The most likely candidates are patients who have a rare form of neurofibromatosis and acoustic neuromas on both acoustic nerves. Martuza, R. L. et al., “Neurofibromatosis 2 (bilateral Acoustic Neurofibromatosis),” N. Engl. J. Med., 318:684–688, 1988. A small number of these patients are referred regularly to such institutions as the House Ear Institute. Many university medical centers, however, would be unable to identify a single suitable candidate during a full year. In the fourteen years since its initial clinical application at the House Institute, cochlear nucleus implant use and testing has remained quite restricted (less than two implants per year average during the epoch reported in Eisenberg, L. S. et al., “Electrical stimulation of the auditory brainstem structure in deafened adults,” J. Rehab. Res. 24:9–22, 1987.
Treating Deafness
Devices designed to treat deafness must take into consideration the underlying cause of deafness. For example, a patient with defective cochlea 110 who still has a functional acoustic nerve, may benefit from an artificial cochlea (cochlear implant). However, if the acoustic nerve is damaged and cannot carry electrical signals, then the problem is “too far downstream” in the signal processing sequence for a cochlear implant to be effective. In that situation, artificial signals must enter the auditory system “beyond the block” either in brain stem 114 or in auditory cortex 150.
Parkinson's Disease
Parkinson's disease is a neuropathological condition of unknown aetiology which afflicts approximately 1 million individuals in the U.S. alone. Symptoms include a paucity of spontaneous movement (bradykinesia), rigidity, and tremor, which in many cases can be very disabling. The average age of onset is 57, with about 30% of cases being diagnosed before age 50. Since the 1960's a number of different drugs have been used for the treatment of Parkinson's disease. Drug treatment of Parkinson's disease may ameliorate some of the symptoms, but does not provide a cure for the disease. Furthermore, drugs used for the treatment of Parkinson's disease tend to become less effective in alleviating symptoms over time and often result in severe side effects. For example, L-dopa which has been widely used for the treatment of Parkinson's disease over the past 30 years, is associated with side effects which include uncontrollable muscular contraction of the limbs and face. And, with the passage of time many, perhaps all, patients fail to respond well to L-dopa treatment.
Prior Art Surgical Treatment of Parkinson's Disease
Surgical treatment by neurosurgeons to treat Parkinson's disease has its roots in the observation that some patients exhibited decreased symptoms after experiencing a mild stroke. A widely accepted explanation for this observation is that the stroke caused destruction of fiber tracts or groups of neurons which had been conducting or generating abnormal signals. Early attempts to treat Parkinson's disease by selectively inactivating certain parts of the brain gave mixed results. The poor results obtained can be ascribed to a number of causes, particularly including poor targeting of brain tissue to be inactivated and imprecision in the design and use of the surgical probes.
Neurosurgeons at a number of medical centers worldwide are currently performing stereotactic thalamotomy or pallidotomy for the treatment of Parkinson's disease, in which regions within the target tissue (thalamus or globus pallidus) of the patient's brain are surgically accessed, physiologically monitored, and targeted for localized tissue destruction (L. Y. Laitinen, et al., “Leksell's Posteroventral Pallidotomy in the Treatment of Parkinson's Disease,” J. Neurosurg., 76, 53–61 (1992), R. P. Iacono, et al., “The Results, Indications, and Physiology of Posteroventral Pallidotomy for Patients with Parkinson's Disease,” Neurosurgery, 36, 1118–1127 (1995), and references cited therein).
FIG. 12A shows the gross morphology, relative size and approximate location of the globus pallidus. The globus pallidus is a conical subcortical structure which is involved in the control of movement. FIG. 12B shows the gross morphology, relative size and approximate location of the thalamus. The thalamus is a relatively large ovoid body which, inter alia, relays sensory stimuli to the cerebral cortex.
Prior Art Stereotactic Pallidotomy
The currently used prior art procedure is quite complex and cumbersome. Briefly, it involves a preliminary step of obtaining microelectrode recordings from specific regions within the globus pallidus. Then, depending on the electrical potential(s) recorded from the particular region under study, the microelectrode is removed, and a macroelectrode is introduced into the same region of the globus pallidus to create a lesion thereat, thereby causing localized tissue destruction and irreversible inactivation of neurons in that region. This process must be repeated a number of times in order to obtain an appropriate “sample” of the globus pallidus.
According to the prior art stereotactic techniques, the trajectories of the introduced electrodes are perpendicular to the long axis of the globus pallidus, as shown in FIG. 12C. The prior art techniques therefore entail the surgeon making several passes through normal brain tissue. In addition, the electrode trajectories of the prior art techniques are the least useful with respect to sampling the target volume. Furthermore, the use of separate electrodes for monitoring neuron physiology (microelectrode) and for producing lesions (macroelectrode) is inefficient, time consuming, and is prone to error in positioning the macroelectrode.
Hypothalamic Obesity Probe
While malnutrition is known as a serious problem in many underdeveloped nations, obesity has been referred to as the major nutritional disorder of the developed world. This disorder is extremely prevalent: approximately one in three, or about 33%, of the population in the U.S. are overweight. Obesity is known to have serious adverse effects on health, and is associated with increased morbidity and mortality from a number of diseases and physiological conditions, including cardiovascular disease, stroke, coronary infarction, hypertension, diabetes, and hypercholesterolemia. {See, for example, Manson et al., N. Engl. J. Med. 333:677–685; 1995 OPTIONALLY OMIT CITATION.} In most cases a quantitative relationship exists showing a positive correlation between body weight of an individual of a given height and a particular health risk to that individual, i.e., the heavier the individual, the greater the risk. Apart from health-related factors discussed above, obesity is also undesirable in that it restricts mobility of the afflicted individual, and in addition can be a source of unacceptance, ridicule, and discrimination in certain societies.
Simply stated, weight gain in the otherwise healthy person is typically due to a net positive caloric balance, ie., the total caloric content of food ingested exceeds the number of calories “burned” during metabolism over a defined period of time. It is not uncommon for an obese person to be as much as 30 Kg overweight. In order to lose 30 Kg of adipose tissue (fat), a negative net energy balance of about 210,000 Kcal (210,000 calories) is required. Naturally, it will require a period of several months to achieve weight loss on these proportions.
Current approaches to treating obesity include one or more of the following: adherence to a reduced calorie diet (with or without treatment with appetite suppressant drugs); lifestyle change, such as increased exercise regime; and surgery. The approach adopted for any one individual will depend on the degree of obesity, age of the individual, and other factors.
Morbid obesity is a prevalent, debilitating, and life threatening disorder for which surgical procedures may be indicated. Current surgical treatments involving the gastrointestinal tract seek to decrease the patient's ability to absorb calories from ingested caloric material (food and beverages). Such treatments comprise major surgical procedures which themselves carry considerable risk of mortality and mortality, and in addition such procedures often prove to be ineffective.
Apart from surgical procedures for the treatment of obesity, a number of attempts have been made to treat certain disturbances or disorders, including appetite disorders, by various forms of electrical stimulation of the head, CNS, or brain of a patient. For example, U.S. Pat. No. 5,540,734 discloses electrical stimulation of one or both of the trigeminal and glossopharyngeal nerves via one or more electrodes attached thereto. Such electrical stimulation is disclosed to serve as a means to treat, control or prevent various disorders (psychiatric, neurological, etc.), including eating disorders such as compulsive overeating. U.S. Pat. No. 5,443,710 discloses a method for treating various disorders, including appetite intrusiveness, by use of electroencephalographic disentrainment feedback to “exercise” the patient's brain, wherein the term “disentrainment” refers to the disruption of entrained brain wave patterns. U.S. Pat. No. 5,332,401 discloses an apparatus and method for transcranial electrotherapy (TCET), wherein the apparatus includes a skin electrode mounting system, e.g. for attachment to the earlobes of a patient. An electrical conductor for application to the skin comprises a generally conical needle point capable of penetrating the epidermis to provide good electrical contact over a small area. The disclosed apparatus and method can be used to treat a number of disorders including appetite disturbance; TCET administered at the appropriate time of day could be used to suppress (or enhance) appetite. U.S. Pat. No. 5,263,480 and U.S. Pat. No. 5,188,104 both to Wernicke disclose a method for treating patients having a compulsive eating disorder, such as compulsive eating to excess and compulsive refusal to eat (anorexia nervosa). The method includes the steps of detecting a preselected event indicative of an imminent need for treatment of the disorder, and applying a predetermined stimulating signal to the patient's vagus nerve (tenth cranial nerve). U.S. Pat. No. 5,084,007 discloses a method for remediating imbalances or deficiencies in neuroactive substances that modulate neurohumoral mechanisms. An object of the invention of the '007 is to provide a method for use in, e.g. stress-related disorders such as certain forms of obesity. The method involves the concomitant administration of transcranial electrostimulation (TE) and a neuroactive chemical promoter, to produce a greater effect than either treatment would produce acting individually. U.S. Pat. No. 4,646,744 discloses a method for treating various disorders or afflictions, e.g. stress, drug addictions, appetite disturbances, insomnia, etc., the method including the transcranial application of electrical signals to the patient. U.S. Pat. No. 3,762,396 discloses a method for treating various psychosomatic ailments by the application of synchronized energetic stimuli to the patient. In particular, electric current pulses are passed through the brain stem via electrodes attached to the back of the head and forehead. A second stimulus of electric current pulses is passed through the optic nerve via electrodes attached to the temples and forehead. The electrodes are mounted on a single elastic band which encircles the head of the patient, and provides electrode contact pressure.
Similarly, a number of attempts have been made to treat various disorders, including eating disorders, using certain drug therapies. For example, U.S. Pat. No. 5,554,643 discloses a series of synthetic peptide-related compounds which are pro-drugs useful, inter alia, as antipsychotic agents and for the treatment of obesity. The '643 patent refers to drug (amphetamine) delivery (to Sprague Dawley rats) via intracerebral injection cannulae as part of an experiment to demonstrate the usefulness of the disclosed peptide-related compounds as antipsychotic agents, while the disclosed novel compounds themselves are administered via intraperitoneal injection. The '643 also discloses appetite suppressant studies in which the novel compounds are administered intravenously through a cannulated jugular vein. In tests of anxiolytic activity exhibited by the disclosed compounds, pro-drug administration (to mice) is performed subcutaneously, intraperitonealy, or by mouth. U.S. Pat. No. 5,523,306 and U.S. Pat. No. 5,397,788 both also to Horwell et al. disclose substantially the same material as the '643. U.S. Pat. No. 5,399,565 discloses novel substituted pyrazolidinones which exhibit binding to cholecystokinin (CCK) receptors and gastrin receptors in the brain and/or peripheral sites. The pyrazolidinones are CCK and gastrin receptor antagonists which are useful for, inter alia, appetite regulation. The CCK and gastrin receptor antagonists may be administered orally, parenterally, transdermally, or as suppositories. U.S. Pat. No. 5,340,802 discloses peptide analog type-B cholecystokinin (CCK) receptor ligands which are useful for treating various disorders, including eating disorders related to appetite control. The compounds of the '802 may be administered in a number of ways, including orally, parenterally (injectable preparations), subcutaneously, topically, and via liposomes. U.S. Pat. No. 5,262,178 discloses a method and therapeutic composition for the treatment of pathological disorders associated with endogenous peptides by the administration of enkephalinase and novel forms thereof. Enkephalinase is implicated in the hydrolysis of endogenous enkephalins in brain tissue, while the effects of enkephalins include gastrointestinal function and increasing appetite. (Administration may be transdermal, intramuscular, intravenous, subcutaneous, intranasal, intraarticular injection, as a topical preparation for local therapy, by aerosol inhalation, by intravascular infusion, and by microparticulate delivery systems, e.g. liposomes.) U.S. Pat. No. 5,120,713 discloses a method for treating obese patients by administering to the patient both an alpha-2-adrenergic agonist, e.g. clonidine, and a growth hormone releasing peptide, e.g. growth hormone releasing hormone (GHRH), to restore or enhance growth hormone release in such patients. Typically clonidine is administered orally, preferably about 1 hour prior to administering the growth hormone releasing peptide, while GHRH is typically administered by injection (i.v. or s.c.).
In previous animal studies, direct microinjections of neuropeptide Y (NPY) into various discrete hypothalamic nuclei of the rat consistently increased food intake in all regions examined (Jolicoeur, F. B., et al., “Mapping of hypothalamic sites involved in the effects of NPY on body temperature and food intake,” Brain Research Bulletin, 36:125–129, 1995).
Previous studies have demonstrated that an electrical stimulation device can be safely implanted into the human hypothalamus using standard stereotactic techniques. See for example Dieckman, G, et al., “Influence of stereotactic hypothalamy on alcohol and drug addiction”, Appl. Neurophysiol., 41:93–98, 1978; Mayanagi, Y., et al., “The posteromedial hypothalamus and pain, behavior, with special reference to endocrinological findings”, Appl. Neurophysiol. 41:223–231, 1978; Nakao, H., Emotional behavior produced by hypothalamic stimulation”, Am. J. Physiol. 194:411418, 1958; Sano, K. “Effects of stimulation and destruction of the posterior hypothalamus in cases of behavior disorders and epilepsy”, Special topics in stereotaxis. Berlin Symposium 1970. Hippokrates Verlag Stuttgart.
Similarly, prior art studies have demonstrated that manipulation of the human hypothalamus may effect changes in appetite. Thus Sano observed a marked increase in appetite, resulting in weight gain, as an unintended side effect of certain hypothalamic lesions (Sano, K. “Effects of stimulation and destruction of the posterior hypothalamus in cases of behavior disorders and epilepsy”, Special topics in stereotaxis. Berlin Symposium 1970. Hippokrates Verlag Stuttgart).
Animal studies directed at determining the effects of periodic hypothalamic electrical stimulation on weight gain in rats, have provided strong indirect evidence of the feasibility of using electrical stimulation of the hypothalamus therapeutically in obese humans to decrease body weight. For example, Bielejaw, et al., and Stenger, et al. found that periodic electrical stimulation of specific loci within the hypothalamus with a 50 Hz stimulation current reduces weight gain in rats. (Bielejaw, C., et al., “Factors that contribute to the reduced weight gain following chronic ventromedial hypothalamic stimulation”, Behavioral Brain Research 62:143–148, 1994; Stenger, J., et al., “The effects of chronic ventromedial hypothalamic stimulation on weight gain in rats”, Physiol. Behav. 50:1209–1213, 1991). In these animal studies, episodic periods of electrical stimulation were delivered to the rat hypothalamus from a single contact electrode coupled to an external stimulation source, as opposed to a chronic indwelling, multicontact electrode stimulation system contemplated by Applicant for human therapeutic use.
The above references are incorporated by reference herein where appropriate for appropriate teachings of additional or alternative details, features and/or technical background.